Although NF-kB has been studied intensively in the context of immunity, inflammation and cancer, far less is understood about the function of NF-?B in the nervous system. In the central nervous system, NF-kB signaling system has been implicated in neurodegenerative disease, epilepsy, and neuronal plasticity. At the neuromuscular junction, activation of NF-kB has been implicated in the mechanisms of muscle wasting associated with neurodegenerative disease (dystrophies and cachexia) and denervation. Despite these observations, the cellular and molecular mechanisms that activate NF-kB signaling within the nervous system remains to be clearly defined. We recently demonstrated that NF- kB/Dorsal, IkB/Cactus and IRAK/Pelle kinase function within postsynaptic muscle to control glutamate receptor density at the Drosophila NMJ, a process relevant to the function of NF-kB at the vertebrate NMJ (Heckscher and Davis, in review). We now have preliminary data identifying a trans-synaptic signaling system that could control NF-kB at the NMJ. In a forward genetic screen we identified mutations in a secreted ligand (TNFa) and its postsynaptic receptor (TNFR2) that impair GluR abundance at the Drosophila NMJ. We present preliminary data that the TNF-alpha gene is expressed in peripheral glia that reside near the NMJ, and that this source of TNF-alpha is necessary and sufficient to control GluR levels. In addition, it has been established that the TNFR2 receptor is expressed in Drosophila muscle. Thus, we hypothesize that the TNF-a and TNFR2 genes define a new, glia-to-muscle, trans-synaptic signaling system at the NMJ. Importantly, it has been demonstrated that the TNFR2 receptor can activate downstream NFkB signaling in other Drosophila tissues. Therefore, we hypothesize the existence of a conserved, glial-to-muscle signaling system that controls GluR levels and neuromuscular function during postembryonic development. We propose experiments to define and elaborate upon this signaling system at the Drosophila NMJ. Given that these signaling molecules are highly evolutionarily conserved, we predict that our data will have direct relevance to the function of NF-kB during neural disease and injury in mammals. PUBLIC HEALTH RELEVANCE: In the nervous system, NF-kB signaling system has been implicated in the mechanisms of neurodegenerative disease, epilepsy, and the response to neuronal injury. Despite the importance of this evolutionarily conserved signaling system, very little is known about how NF- kB participates in these diverse processes. We propose experiments that will not only define how NF-kB is activated in the nervous system, but will also define an output for NF-kB signaling that may be directly relevant to the role of NF-kB during injury and disease.